Identification of clinical factors related to antibody‐mediated immune response to the subfornical organ

Abstract

Objective We recently reported cases of adipsic hypernatremia caused by autoantibodies against the subfornical organ in patients with hypothalamic‐pituitary lesions. This study aimed to clarify the clinical features of newly identified patients with adipsic hypernatremia whose sera displayed immunoreactivity to the mouse subfornical organ. Design Observational cohort study of patients diagnosed with adipsic hypernatremia in Japan, United States, and Europe. Methods The study included 22 patients with adipsic hypernatremia but without overt structural changes in the hypothalamic‐pituitary region and congenital disease. Antibody response to the mouse subfornical organ was determined using immunohistochemistry. The clinical characteristics were compared between the patients with positive and negative antibody responses. Results Antibody response to the mouse subfornical organ was detected in the sera of 16 patients (72.7%, female/male ratio, 1:1, 12 pediatric and 4 adult patients). The prolactin levels at the time of diagnosis were significantly higher in patients with positive subfornical organ (SFO) immunoreactivity than in those with negative SFO immunoreactivity (58.9 ± 33.5 vs. 22.9 ± 13.9 ng/ml, p < .05). Hypothalamic disorders were found in 37.5% of the patients with positive SFO immunoreactivity. Moreover, six patients were diagnosed with rapid‐onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation/neural tumor syndrome after the diagnosis of adipsic hypernatremia. Plasma renin activity levels were significantly higher in patients with serum immunoreactivity to the Nax channel. Conclusions The patients with serum immunoreactivity to the SFO had higher prolactin levels and hypothalamic disorders compared to those without the immunoreactivity. The clinical characteristics of patients with serum immunoreactivity to the subfornical organ included higher prolactin levels and hypothalamic disorders, which were frequently associated with central hypothyroidism and the presence of retroperitoneal tumors.

Autoimmunity Related to Adipsic Hypernatremia and ROHHAD Syndrome

“…Hyperhidrosis, cold limbs, and mild dehydration may occur [1,2]. In addition to an increase in serum Na levels and serum osmolality, an increase in prolactin levels, an increase in the frequency of hypothalamic disorders, and an increase in retroperitoneal tumors have been reported [28]. Moreover, our study revealed that plasma renin activity was significantly higher in the anti-Nax antibody-positive cases.…”

“…Interestingly, recent reports have identified antibodies to SFO and Na x antibodies in patients with clinically diagnosed autoimmune hypernatremia and ROHHAD syndrome. From this, it is possible that some patients in both disease groups develop the disease by a common autoimmune mechanism (Figure 1) [28]. There have been some recent reports supporting the autoimmune mechanism in RO-HHAD syndrome.…”

“…First, the presence or absence of symptoms at birth, the presence or absence of abnormal water metabolism, including Na levels, and the presence or absence of hyperprolactinemia are mentioned [29]. On the other hand, some autoimmunity and acquired factors, such as anti-SFO, anti-hypothalamus, and anti-ZSCAN1 autoantibodies, can be inferred in addition to the genetic predisposition [21,28,30].…”

“…According to the autopsy report, hypothalamic infiltrates involved multiple regions, including the anterior, paraventricular, arcuate, and ventromedial nuclei [18]. There are also reports of the identification of anti-Na x and anti-SFO antibodies in patients diagnosed with ROHHAD syndrome [28]. It has also been reported that the prolactin level was significantly higher in antibody-positive patients, regardless of the clinical diagnosis, and it is considered that the hyperprolactinemia observed in ROHHAD syndrome so far is also consistent with this concept [28].…”

“…Moreover, our study revealed that plasma renin activity was significantly higher in the anti-Nax antibody-positive cases. In cases with hypothalamic syndrome, rapid-onset obesity, weight gain tendency with or without overeating, and insomnia symptoms are observed; some cases are also diagnosed with Attention-Deficit Hyperactivity Disorder [28]. There is also a complication of sleep apnea syndrome due to obesity.…”